Synapses can change their efficacy through synaptic plasticity. Long-lasting forms of synaptic plasticity (such as long-term potentiation and long-term depression of synaptic transmission) are important cellular mechanisms underlying information storage in the brain and the establishment of proper neural circuits during development. In this project, we investigated the mechanism underlying long-term depression of synaptic transmission. Our study shows that macroautophagy (autophagy hereinafter) plays an important role in LTD. Autophagy is a cellular process by which cytoplasmic components and organelles are delivered to lysosomes for degradation. Autophagy removes misfolded or aggregated proteins and defective organelles. Dysfunctional autophagy has been associated with neurological disorders. Autophagy is also essential for the development and function of synapses. It enables developmental pruning of dendritic spines (subcellular structures accommodating postsynaptic components), regulates presynaptic structure and dopamine release, and regulates degradation of postsynaptic receptors. Autophay is initiated by the formation of a phagophore (the isolation membrane). The phagophore expands into autophagosomes (a double membrane structure) to sequester the cargo, and then fuses with lysosomes to become an autolysosome where the cargo is degraded. These processes are orchestrated by more than 30 autophagy-related (Atg) proteins and multiple signaling pathways. Mechanistic target of rapamycin complex 1 (mTORC1) is the best-characterized regulator of autophagy induction in mammalian cells. It inhibits autophagy initiation by phosphorylating ULK1/2 (Unc-51-like kinase) and Atg13. Using mTOR inhibitors and knockout mice with deficient autophagy, we found that autophagic fluxis changed during LTD and this in turn leads toAMPA receptor endocytosis. During this reporting period, we investigated the mechanism by which autophagy is regulated in LTD and how autophagy contributes to LTD. We also examined the behavior of mice in which autophagic flux is altered. 2. The mechanism by which the schizophrenia risk gene dysbindin contributes to synaptopathology in schizophrenia. Dysbindin is a coiled-coil domain containing protein, initially discovered as a dystrophin-binding protein and later found to be one of eight subunits of biogenesis of lysosome-related organelles complex 1 (BLOC-1). Single-nucleotide polymorphisms of the dysbindin gene (Dtnbp1) have been associated with higher risk for schizophrenia, and the postmortem brains of schizophrenia patients consistently exhibit low levels of dysbindin proteins and mRNAs. Our earlier work shows that dysbindin contributes to the establishment of neuronal connectivity by regulating the development of dendritic protrusions, including dendritic spines (tiny dendritic protrusions where excitatory synapses are formed) and filopodia (long, thin protrusions that predominant in young neurons). Dysbindin, therefore, may confer the risk for schizophrenia by regulating the development of dendritic spines. Psychiatric disease is commonly precipitated by psychological stress. It is largely unclear how stress interacts with genetic risk factors in the etiology of schizophrenia. In this project, we investigated the effect of stress on the behavior of dysbindin null mutant mice. We found that mild stress that does not significantly affect the behavior of wild-type mice induces behaviors that are related to the symptom of schizophrenia in mutant mice. We recorded in the brain slices of stressed mice and found that stress alters synaptic physiology in mutant but not in wild-type mice. During this reporting period, we examined the effect of stress on synaptic physiology in sdy mice. We also set up a two-photon microscopy system to take images of dendritic spines in awake, behaving mice. We will use this system to investigate whether and how stress affects the number, morphology and dynamics of dendritic spines in the brain.